Bial

About: Bial is a company organization based out in Porto, Portugal. It is known for research contribution in the topics: Eslicarbazepine acetate & Catechol-O-methyl transferase. The organization has 321 authors who have published 591 publications receiving 30583 citations.

Evaluation of the permeability and P-glycoprotein efflux of carbamazepine and several derivatives across mouse small intestine by the Ussing chamber technique.

Abstract: Summary Purpose: The rational discovery and development of new antiepileptic drugs (AEDs) with safer therapeutic index and better pharmacokinetic properties is still warranted nowadays. Because the long-term management of epilepsy is attained by means of orally administered AEDs, investigation of their potential to be well absorbed at the intestinal level is mandatory. Moreover, involvement of the efflux transport mediated by P-glycoprotein (P-gp) may compromise the systemic and central nervous system disposition of AEDs. Therefore, this study aimed at characterizing mouse jejunal passive transport and the possible active efflux mediated by P-gp of a series of dibenz[b,f]azepine-5-carboxamide derivatives (carbamazepine [CBZ], oxcarbazepine [OXC], S-licarbazepine [S-Lic], R-licarbazepine [R-Lic], carbamazepine-10,11-epoxide [CBZ-E], 10,11-trans-dihydroxy-10,11-dihydro-carbamazepine [trans-diol], and BIA 2-024), which comprise some AEDs and metabolites. Methods: Permeation studies were performed with freshly excised mouse jejunum segments mounted in Ussing chambers. Absorptive (M-S) and secretive (S-M) transports were analyzed with and without verapamil, which is a P-gp inhibitor widely recognized. Apparent permeability coefficients (Papp) in both directions and in absence or presence of verapamil were determined for each test compound. The in vitro method was validated using five controls that included high and low permeable markers with known absorption fraction (Fa) and also well-known P-gp substrates. The integrity of intestinal membrane was guaranteed during the assay by measuring the transepithelial electrical resistance. Key Findings: The correlation obtained between Papp(M-S) and Fa of references was high (r2 = 0.9945), and could be used to classify the derivatives according to Biopharmaceutical Classification System: CBZ and OXC were the only classified as highly permeable. The Papp(S-M) of OXC, CBZ-E, R-Lic, and BIA 2-024 were significantly higher than their Papp(M-S). After verapamil addition, their Papp(S-M) lowered while Papp(S-M) increased, suggesting the involvement of P-gp on the transport of those compounds across mouse jejunum segments. In opposition, CBZ, S-Lic, and trans-diol presented no statistical differences between the Papp values reported in both directions, with or without verapamil. The results reported herein suggest that differences in biodisposition of S-Lic and R-Lic might result from their distinct interaction with P-gp. Significance: The Ussing chamber model used herein showed to be useful for predicting Fa of AEDs and the involvement of efflux transport, namely P-gp, on their absorption. This is an important achievement as compounds that are not transported by P-gp may offer advantages when used in patients with pharmacoresistant epilepsy.

Allergy to human seminal fluid: Cross-reactivity with dog dander

Abstract: Background Human seminal plasma (HSP) allergy is uncommon, with symptoms ranging from vulvovaginal pruritus to life-threatening anaphylaxis. Although several seminal plasma allergens have been reported and their molecular masses have been estimated to range between 12 and 75 kd, the prostate-specific antigen (PSA) has recently been identified as a causative allergen. Given that in a large number of cases symptoms appeared during or after the first intercourse, a cross-reactivity phenomenon might be implicated. Objective We sought to assess the presence of IgE cross-reactivity among proteins from dog epithelium and HSP and to attempt to identify the allergens involved. Methods Forty-one patients with dog epithelium allergy were selected. One of them experienced anaphylaxis in contact with her husband's seminal plasma. Skin prick tests, serum specific IgE measurements, SDS-PAGE immunoblotting, and inhibition tests were performed to study the pattern of IgE-binding proteins and the potential cross-reactivity between HSP and dog epithelium. Mass spectrometry was carried out to identify the protein involved in allergy reactions. Results Twenty-four percent of the sera from patients with dog epithelium allergy recognized an IgE-binding band of 28 kd in HSP immunoblotting. Mass spectrometry identified this band as the PSA. SDS-PAGE immunoblotting-inhibition showed a complete IgE-binding inhibition when sera from these patients were preincubated with dog dander extract. Conclusions IgE cross-reactivity among proteins from dog dander and human PSA is demonstrated.

The major allergen of Alternaria alternata (Alt a 1) is expressed in other members of the Pleosporaceae family

Abstract: There is general consensus regarding the scarce cross-reactivity existing between Alternaria alternata and other allergenic moulds such as Aspergillus fumigatus, Penicillium notatum or Cladosporium herbarum. However, A. alternata has been shown to have a very significant level of allergenic cross-reactivity with other fungi belonging to the Pleosporaceae family. To date, no biological identity or homologies with other proteins have been described for Alt a 1, and it remains unclear whether the major allergen Alt a 1 contributes to the cross-reactivity shown for these moulds. Specific quantification of Alt a 1 in culture filtrates of Stemphylium botryosum, Ulocladium botrytis, Curvularia lunata, Alternaria tenuissima, C. herbarum, Penicillium chrysogenum and Asp. fumigatus, and immunoblotting using culture filtrate extracts from the above-mentioned moulds and rabbit serum anti-recombinant Alt a 1 have shown significant amounts of Alt a 1 in culture filtrates as well as antigenic components ranging from 14 to 20 kDa that strongly react with the specific serum for all taxonomically related species (Pleosporaceae family). No reactions were revealed in culture filtrates of Cladosporium, Penicillium and Aspergillus. These results restrict the cross-reactivity phenomenon due to Alt a 1 to the scope of the taxonomical term of family.

Neutrophils as a novel source of eosinophil cationic protein in IgE-mediated processes.

Abstract: The production of eosinophil cationic protein (ECP) in IgE-mediated diseases has been associated mainly with eosinophils, although no IgE-dependent ECP release has been observed in these cells. Because there is increasing evidence of neutrophil participation in allergic processes, we have examined whether human neutrophils from allergic patients were able to produce ECP by an IgE-dependent mechanism. After challenge with specific Ags to which the patients were sensitized, ECP release was detected in the culture medium. Furthermore, intracellular protein was detected by flow cytometry, immunofluorescence staining, and Western blotting. Expression at both mRNA and de novo protein synthesis were detected, respectively, by RT-PCR and radiolabeling with (35)S. Ag effect was mimicked by cell treatment with anti-IgE Abs or Abs against FcepsilonRI and galectin-3 (FcepsilonRI>galectin-3), but not against FcepsilonRII. These observations represent a novel view of neutrophils as possible source of ECP in IgE-dependent diseases.

Methods and results of a search for gravitational waves associated with gamma-ray bursts using the GEO 600, LIGO, and Virgo detectors

Abstract: In this paper we report on a search for short-duration gravitational wave bursts in the frequency range 64 Hz-1792 Hz associated with gamma-ray bursts (GRBs), using data from GEO600 and one of the LIGO or Virgo detectors. We introduce the method of a linear search grid to analyse GRB events with large sky localisation uncertainties such as the localisations provided by the Fermi Gamma-ray Burst Monitor (GBM). Coherent searches for gravitational waves (GWs) can be computationally intensive when the GRB sky position is not well-localised, due to the corrections required for the difference in arrival time between detectors. Using a linear search grid we are able to reduce the computational cost of the analysis by a factor of O(10) for GBM events. Furthermore, we demonstrate that our analysis pipeline can improve upon the sky localisation of GRBs detected by the GBM, if a high-frequency GW signal is observed in coincidence. We use the linear search grid method in a search for GWs associated with 129 GRBs observed satellite-based gamma-ray experiments between 2006 and 2011. The GRBs in our sample had not been previously analysed for GW counterparts. A fraction of our GRB events are analysed using data from GEO600 while the detector was using squeezed-light states to improve its sensitivity; this is the first search for GWs using data from a squeezed-light interferometric observatory. We find no evidence for GW signals, either with any individual GRB in this sample or with the population as a whole. For each GRB we place lower bounds on the distance to the progenitor, assuming a fixed GW emission energy of $10^{-2} M_{\odot}c^{2}$, with a median exclusion distance of 0.8 Mpc for emission at 500 Hz and 0.3 Mpc at 1 kHz. The reduced computational cost associated with a linear search grid will enable rapid searches for GWs associated with Fermi GBM events in the Advanced detector era.